7e6v
The crystal structure of foot-and-mouth disease virus(FMDV) 2C protein 97-318aa
Structural highlights
FunctionPOLG_FMDS2 Autocatalytically cleaves itself from the polyprotein at the L/VP0 junction. Also cleaves the host translation initiation factors EIF4G1 and EIF4G3, in order to shut off the capped cellular mRNA transcription. Plays a role in counteracting host innate antiviral response using diverse mechanisms. Possesses a deubiquitinase activity acting on both 'Lys-48' and 'Lys-63'-linked polyubiquitin chains. In turn, inhibits the ubiquitination and subsequent activation of key signaling molecules of type I IFN response such as host RIGI, TBK1, TRAF3 and TRAF6. Inhibits host NF-kappa-B activity by inducing a decrease in RELA mRNA levels. Cleaves a peptide bond in the C-terminus of host ISG15, resulting in the damaging of this modifier that can no longer be attached to target proteins. Also cleaves host G3BP1 and G3BP2 in order to inhibit cytoplasmic stress granules assembly.[UniProtKB:P03305][UniProtKB:P03308] Lies on the inner surface of the capsid shell. After binding to the host receptor, the capsid undergoes conformational changes. Capsid protein VP4 is released, capsid protein VP1 N-terminus is externalized, and together, they shape a pore in the host membrane through which the viral genome is translocated into the host cell cytoplasm. After genome has been released, the channel shrinks.[UniProtKB:P03300] Forms an icosahedral capsid of pseudo T=3 symmetry with capsid proteins VP1 and VP3. The capsid is composed of 60 copies of each capsid protein organized in the form of twelve pentamers and encloses the viral positive strand RNA genome (By similarity). Upon acidifcation in the endosome, dissociates into pentamers (By similarity).[UniProtKB:P03305][UniProtKB:P03306] Forms an icosahedral capsid of pseudo T=3 symmetry with capsid proteins VP0 and VP3. The capsid is composed of 60 copies of each capsid protein organized in the form of twelve pentamers and encloses the viral positive strand RNA genome (By similarity). Upon acidifcation in the endosome, dissociates into pentamers (By similarity).[UniProtKB:P03305][UniProtKB:P03306] Forms an icosahedral capsid of pseudo T=3 symmetry with capsid proteins VP2 and VP3. The capsid is composed of 60 copies of each capsid protein organized in the form of twelve pentamers and encloses the viral positive strand RNA genome. Mediates cell entry by attachment to an integrin receptor, usually host ITGAV/ITGB6. In addition, targets host MAVS to suppress type I IFN pathway (By similarity). Upon acidifcation in the endosome, dissociates into pentamers (By similarity).[UniProtKB:P03305][UniProtKB:P03306] Mediates self-processing of the polyprotein by a translational effect termed 'ribosome skipping'. Mechanistically, 2A-mediated cleavage occurs between the C-terminal glycine and the proline of the downstream protein 2B. In the case of foot-and-mouth disease virus, the 2A oligopeptide is post-translationally 'trimmed' from the C-terminus of the upstream protein 1D by 3C proteinase.[UniProtKB:P03305] Plays an essential role in the virus replication cycle by acting as a viroporin. Creates a pore in the host reticulum endoplasmic and as a consequence releases Ca2+ in the cytoplasm of infected cell. In turn, high levels of cytoplasmic calcium may trigger membrane trafficking and transport of viral ER-associated proteins to viroplasms, sites of viral genome replication.[UniProtKB:P03305] Associates with and induces structural rearrangements of intracellular membranes. Triggers host autophagy by interacting with host BECN1 and thereby promotes viral replication. Participates in viral replication and interacts with host DHX9. Displays RNA-binding, nucleotide binding and NTPase activities (Probable). May play a role in virion morphogenesis and viral RNA encapsidation by interacting with the capsid protein VP3.[UniProtKB:P03305][1] Plays important roles in virus replication, virulence and host range. Cooperates with host DDX56 to inhibit IRF3 nuclear translocation and subsequent type I interferon production.[UniProtKB:P03305] Covalently linked to the 5'-end of both the positive-strand and negative-strand genomic RNAs. Acts as a genome-linked replication primer.[UniProtKB:P03305] Covalently linked to the 5'-end of both the positive-strand and negative-strand genomic RNAs. Acts as a genome-linked replication primer.[UniProtKB:P03305] Covalently linked to the 5'-end of both the positive-strand and negative-strand genomic RNAs. Acts as a genome-linked replication primer.[UniProtKB:P03305] Cysteine protease that generates mature viral proteins from the precursor polyprotein. In addition to its proteolytic activity, binds to viral RNA and thus influences viral genome replication. RNA and substrate bind cooperatively to the protease.[UniProtKB:P03305] RNA-directed RNA polymerase 3D-POL replicates genomic and antigenomic RNA by recognizing replications specific signals. Covalently attaches UMP to a tyrosine of VPg, which is used to prime RNA synthesis. The positive stranded RNA genome is first replicated at virus induced membranous vesicles, creating a dsRNA genomic replication form. This dsRNA is then used as template to synthesize positive stranded RNA genomes. ss(+)RNA genomes are either translated, replicated or encapsidated.[UniProtKB:P03305] Publication Abstract from PubMedThe foot-and-mouth disease virus (FMDV) 2C protein shares conserved motifs with enterovirus 2Cs despite low sequence identity. Here, we determine the crystal structure of an FMDV 2C fragment to 1.83 A resolution, which comprises an ATPase domain, a region equivalent to the enterovirus 2C zinc-finger (ZFER), and a C-terminal domain harboring a loop (PBL) that occupies a hydrophobic cleft (Pocket) in an adjacent 2C molecule. Mutations at ZFER, PBL, and Pocket affect FMDV 2C ATPase activity and are lethal to FMDV infectious clones. Because the PBL-Pocket interaction between FMDV 2C molecules is essential for its functions, we design an anti-FMDV peptide derived from PBL (PBL-peptide). PBL-peptide inhibits FMDV 2C ATPase activity, binds FMDV 2C with nanomolar affinity, and disrupts FMDV 2C oligomerization. FMDV 2C targets lipid droplets (LDs) and induces LD clustering in cells, and PBL-peptide disrupts FMDV 2C-induced LD clustering. Finally, we demonstrate that PBL-peptide exhibits anti-FMDV activity in cells. An anti-picornaviral strategy based on the crystal structure of foot-and-mouth disease virus 2C protein.,Zhang C, Yang F, Wojdyla JA, Qin B, Zhang W, Zheng M, Cao W, Wang M, Gao X, Zheng H, Cui S Cell Rep. 2022 Jul 5;40(1):111030. doi: 10.1016/j.celrep.2022.111030. PMID:35793627[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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